PROJECT SUMMARY The MYC family of oncogenes encodes a set of related transcription factors that are deregulated in the majority of human malignancies. As transcription factors, MYC proteins derive their oncogenicity by regulating the expression of thousands of genes involved in cell growth, metabolism, proliferation, and genome integrity. Preventing MYC from recognizing its target genes has been validated as a broadly effective way to inhibit MYC function and to kill cancer cells, but as of yet there are no small, drug-like, and potent molecules capable of disabling target gene recognition by MYC family proteins. Recently, I participated in a set of studies that demonstrated that target gene recognition by MYC in the context of chromatin depends on its interaction with the prevalent chromatin regulator WDR5. In these studies, we identified WDR5 as a direct MYC-interaction partner, defined precisely how the two proteins interact, and demonstrated that disruption of the MYC?WDR5 interaction attenuates the ability of MYC to bind chromatin and to drive tumorigenesis in mice. Importantly, this study also revealed that properties of the MYC?WDR5 interface make it a viable point for the discovery of small molecule inhibitors that disable chromatin-binding, and target gene regulation, by MYC in cancer cells. The goal of this project is to define how MYC and WDR5 work together on chromatin to select and regulate MYC target genes, and to determine whether disruption of the MYC?WDR5 interaction disables the ability of MYC to promote and sustain lymphomagenesis in mice. Aim 1 will provide high-resolution insight into genes regulated by MYC and WDR5 in lymphoma cells, and delineate the proteins, DNA sequences, and histone modifications that conspire to select MYC target genes in this setting. Aim 2 will directly interrogate the significance of the MYC?WDR5 interaction to lymphoma onset and treatment by asking whether disruption of this interaction blocks lymphomagenesis in mice, and whether disrupting the MYC?WDR5 interaction in the context of a preformed lymphoma promotes tumor regression. Together, these aims will establish a new paradigm for MYC recruitment to chromatin and provide direct evidence for the therapeutic impact of inhibiting the MYC?WDR5 interaction in cancer cells. The didactic graduate program and cancer-rich environment at Vanderbilt University, the guidance from my mentor, Dr. William Tansey, and the superb cohort of collaborators we have assembled for this project will synergize to allow me to complete the proposed studies and receive invaluable training as a scientist. The education, training, collaborations, and career development program detailed in this proposal will strongly support my career objective of becoming an independent, and effective, cancer researcher.